Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, 1040 Drillfield Drive, Blacksburg, Virginia 24061, United States.
Department of Pharmaceutical Sciences, University of Illinois Chicago, 833 S Wood Street, Chicago, Illinois 60612, United States.
ACS Infect Dis. 2024 Nov 8;10(11):3951-3962. doi: 10.1021/acsinfecdis.4c00653. Epub 2024 Oct 28.
The development of parasite resistance to both artemisinin derivatives and their partner drugs jeopardizes the effectiveness of the artemisinin combination therapy. Thus, the discovery of new antimalarial drugs, with new mechanisms of action, is urgently needed. We recently disclosed that β-carboline was orally efficacious in -infected mice and that it showed low cross-resistance between susceptible and four different drug-resistant strains. In this report, we describe the synthesis and antimalarial evaluation of 91 new derivatives of . The asexual blood stage growth inhibition data show a clear preference for a 3,4-dihalogenated, 3,5-dihalogenated, 3,4,5-trichloro-, or 4-trifluoromethyphenyl ring at the C1-position. The most potent compound, 3,4,5-trichlorophenyl-substituted , is twice as potent as . Six potent analogues were assessed for their drug-like properties, and four of these were subjected to barcoded cross-resistance profiling. Compounds , , , and showed no cross-resistance to 32 resistance mutations on the Dd2 genetic background and 10 resistance mutations on the 3D7 genetic background. These data suggest that compounds in this scaffold possess a novel mechanism of antimalarial action.
疟原虫对青蒿素衍生物及其联合用药的耐药性发展，危及青蒿素联合疗法的疗效。因此，急需发现具有新作用机制的抗疟新药。我们最近披露，β-咔啉衍生物在感染的小鼠中具有口服疗效，并且在敏感株和四种不同耐药株之间显示出低交叉耐药性。在本报告中，我们描述了 91 种新的 β-咔啉衍生物的合成和抗疟评估。无性血阶段生长抑制数据表明，C1 位上带有 3,4-二卤代、3,5-二卤代、3,4,5-三氯代或 4-三氟甲基苯基环的化合物具有明显的优势。最有效的化合物 3,4,5-三氯代苯基取代的 β-咔啉衍生物的效力是青蒿素的两倍。对 6 种有效类似物进行了药物样特性评估，其中 4 种进行了条形码交叉耐药性分析。化合物 、 、 和 在 Dd2 遗传背景下对 32 种耐药突变和 3D7 遗传背景下的 10 种耐药突变没有交叉耐药性。这些数据表明，该骨架中的化合物具有一种新的抗疟作用机制。
